PROJECT SUMMARY/ABSTRACT: Triple negative breast cancer (TNBC) is an aggressive and difficult to manage disease that disproportionately afflicts underrepresented minority populations. Tumor cellular heterogeneity is a major source of treatment resistance and resilience, but is poorly understood. Thus, better understanding of tumor heterogeneity will lead to development of therapeutic strategies to treat underrepresented minority TNBC patients. The objective of this proposal is to identify and characterize biomarkers of cell subsets that drive tumor resilience in African- American (AA) patients. The central hypothesis is that differential cell population heterogeneity contributes to disparate TNBC prevalence and treatment outcomes in AA and other underrepresented patient groups. The rationale for the proposed research is that better understanding of tumor cellular heterogeneity will result in new and innovative approaches to TNBC treatment for underrepresented minority TNBC patients. Therefore, the hypothesis will be tested by pursuing the following specific aims: Aim 1) Identification of phenotypic states in AA TNBC with single cell RNA-seq; Aim 2) Associations of candidate biomarker sets with AA TNBC, clinical variables, immune phenotypes, genomic information, and outcomes in a TNBC neoadjuvant trial. The proposed research is innovative, because of the novel approach to use single cell profiling to define and understand novel tumor cell lineages and microenvironment for AA TNBC tumors. The proposed research is significant, because it is expected to advance and expand our understanding of tumor heterogeneity and drug resistance in AA TNBC patients. Such knowledge is a critical foundation for the development of cancer therapies targeting vulnerabilities of tumor heterogeneity in AA TNBC patients.